AZD9291 in Combination With Ascending Doses of Novel Therapeutics

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Know the risks and potential benefits of clinical studies and talk to your health care provider before participating.
Read our disclaimer for details.

The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer.

Condition or disease

Intervention/treatment

Phase

Advanced Non Small Cell Lung Cancer

Drug: Part A - AZD9291 in combination with AZD6094Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)Drug: Part A - AZD9291 in combination with intermittent selumetinibDrug: Part A - AZD9291 in combination with MEDI4736Drug: Part B - AZD9291 in combination with AZD6094Drug: Part B - AZD9291 in combination with selumetinibDrug: Part B - AZD9291 in combination with MEDI4736Drug: Part C - AZD6094 monotherapy (Japan only)Drug: Part C - AZD9291 in combination with AZD6094 (Japan only)Drug: Part D - AZD9291 in combination with AZD6094

Phase 1

Detailed Description:

This is a Phase Ib, open-label, multicentre study of AZD9291 administered orally in combination with novel therapeutics (AZD6094 or selumetinib (AZD6244, ARRY142886)) to patients with EGFRm+ advanced NSCLC. The study has been designed to allow an investigation of the optimal combination dose and schedule whilst ensuring the safety of patients with intensive safety monitoring. There are three main parts to this study; Part A, Combination dose finding and Parts B and D, Dose expansion. Part C, AZD6094 dose finding sub-study in advanced solid tumour patients is ongoing in Japan.

AZD9291 (osimertinib) is a potent irreversible inhibitor of both the single epidermal growth factor receptor sensitising mutation positive (EGFRm+) (tyrosine kinase inhibitor [TKI] sensitivity-conferring mutation) and dual EGFRm+/T790M+ (TKI resistance-conferring mutation) receptor forms of EGFR. AZD9291 therefore has the potential to provide clinical benefit to patients with advanced non-small cell lung cancer (NSCLC) harbouring both the single sensitivity mutations and the resistance mutation following prior therapy with an EGFR TKI. AZD9291 (osimertinib) was awarded FDA accelerated approval in November 2015, followed by conditional approval in the EU, full approval in Japan and additional markets in 2016, for the treatment of patients with EGFR T790M+ NSCLC who have progressed on or after EGFR TKI therapy.

Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.

A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety,Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm+ Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON).

Part A - AZD9291 and AZD6094 administered in different doses to investigate the safety and tolerability of this combination and define the combination dose for further clinical evaluation in Part B.

Other Name: Osimertinib & Savolitinib/Volitinib

Drug: Part B - AZD9291 in combination with AZD6094

Part B - AZD9291 and AZD6094 administered in the dose identified in Part A (AZD9291 80mg OD + AZD6094 600mg OD) to further investigate the safety and tolerability of this combination.

Other Name: Osimertinib & Savolitinib/Volitinib

Drug: Part C - AZD9291 in combination with AZD6094 (Japan only)

Part C combination cohort - AZD9291 80mg OD administered in combination with AZD6094 400mg OD (AZD6094 dose in which DLTs have not been identified in the Japanese monotherapy cohort) in order to confirm the safety, tolerability, pharmacokinetics and preliminary anti-tumor activities of this combination in Japanese subjects. The 400mg OD dosing schedule will be initiated in the first cohort. The dose may be subsequently reduced in further cohorts in response to emerging safety, or PK findings or other reasons identified in the savolitinib programme.

Other Name: Osimertinib & Savolitinib/Volitinib

Drug: Part D - AZD9291 in combination with AZD6094

Part D - AZD9291 80mg OD administered in combination with AZD6094 300mg OD to further evaluate the safety, tolerability, pharmacokinetics and antitumor activity in terms of ORR and PFS in patients with locally advanced or metastatic cMET positive EGFRm+ and T790M-negative NSCLC, following progression on EGFR-TKI treatment. The choice of AZD6094 dose of 300 mg is based on results from preclinical and clinical studies. Clinical testing of the 300 mg OD dose will enable better assessment of impact of lower AZD6094 exposure on overall tolerability and hepatotoxicity risk as well as exploration of the efficacy and overall safety profiles with a dose meaningfully lower than the current dose of 600 mg OD.

Other Name: Osimertinib & Savolitinib/Volitinib

Experimental: Selumetinib

AZD9291 in combination with selumetinib

Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)

Part A - AZD9291 and selumetinib (continuous treatment) administered in different doses to investigate the safety and tolerability of this combination in Asian subjects and to define the combination dose for further clinical evaluation in Part B.

Other Name: Osimertinib & ARRY-142886

Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)

Part A - AZD9291 and selumetinib (continuous treatment) administered in different doses to investigate the safety and tolerability of this combination in non-Asian subjects and to define the combination dose for further clinical evaluation in Part B.

Other Name: Osimertinib & ARRY-142886

Drug: Part A - AZD9291 in combination with intermittent selumetinib

Part A - AZD9291 and selumetinib (intermittent treatment) administered in different doses to investigate the safety and tolerability of this combination and to define the combination dose for further clinical evaluation in Part B.

Other Name: Osimertinib & ARRY-142886

Drug: Part B - AZD9291 in combination with selumetinib

Part B - AZD9291 and selumetinib administered in the dose identified in Part A (AZD9291 80mg OD + selumetinib 75 mg BD intermittent [4 days on/3 days off]) to further investigate the safety and tolerability of this combination.

Other Name: Osimertinib & ARRY-142886

Experimental: MEDI4736

AZD9291 in combination with MEDI4736. Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.

Drug: Part A - AZD9291 in combination with MEDI4736

Part A - AZD9291 and MEDI4736 administered in different doses to investigate the safety and tolerability of this combination and to define the combination dose for further clinical evaluation in Part B.

Note: Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.

Other Name: Osimertinib & Durvalumab

Drug: Part B - AZD9291 in combination with MEDI4736

Part B - AZD9291 and MEDI4736 administered in the dose identified in Part A to further investigate the safety and tolerability of this combination.

Note: Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.

Other Name: Osimertinib & Durvalumab

Experimental: AZD6094 (monotherapy)

AZD6094 in monotherapy (for Japan only)

Drug: Part C - AZD6094 monotherapy (Japan only)

Part C - AZD6094 monotherapy to assess the safety, tolerability and pharmacokinetics of the monotherapy of AZD6094 in Japanese patients with advanced NSCLC.

Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib [ Time Frame: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms. ]

Part A: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.

Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib [ Time Frame: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms. ]

Part B: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib in patients with locally advanced or metastatic NSCLC, who have progressed on prior therapy with an EGFR TKI agent.

Part C monotherapy cohort (Japan only): To investigate and confirm the safety and tolerability of AZD6094 when given orally to Japanese patients with advanced solid malignancies.

Part C combination cohort (Japan only): To investigate the safety and tolerability of AZD9291 when given orally to Japanese patients with EGFRm+ NSCLC in combination with AZD6094 who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.

Part D: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 (300 mg OD) in patients with locally advanced or metastatic EGFRm+ NSCLC.

Secondary Outcome Measures
:

Cmax after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Tmax after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

AUC after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

AUC0-t after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

AUC0-24 after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Terminal half life after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

CL/f after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Volume of distribution after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Cssmax after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Tssmax after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Cssmin after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times for the duration of treatment. ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

AUCss after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

CLss/f after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Rac after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1 ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Time dependency of PK after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1 ]

To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Objective response rate [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]

To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1.

Disease control rate [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]

To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Duration of response [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]

To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Percentage change in tumour size [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]

To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Progression free survival [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]

To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1 Expansion phase only

Overall survival [ Time Frame: Confirmed during the FUP period and at least every 12 weeks until the data cut-off for the primary analysis and determination that no further OS collection is needed, approximately 5 years, death, or full withdrawal of consent, whichever comes first. ]

To obtain a preliminary assessment of overall survival in the AZD9291+AZD6094 combination arms of the study for Parts B and D.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

(summarized due to limitation of characters)

Inclusion Criteria:

Written informed consent

Aged at least 18 years (20 years for Japan)

Histological or cytological confirmation diagnosis of EGFRm+ NSCLC. Confirmation from a previous archival sample that the tumour harbours an EGFRm+ known to be associated with EGFR TKI sensitivity.

Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI (on the last treatment administered prior to enrolling in the study)

Part B cMET+ve patients:

No prior treatment with a 3rd generation TKI: at least one prior line of therapy with 1st or 2nd generation EGFR TKI, but not a 3rd generation (T790M-directed) EGFR TKI.

Prior treatment with a 3rd generation TKI: at least one prior line of therapy with a 3rd generation (T790M-directed) EGFR TKI for EGFRm or T790M+ NSCLC.

Part B cMET-ve patients:

T790M directed EGFR TKI patients only: their immediate prior therapy before entry into this study must be a T790M directed EGFR TKI.

≥2nd line cohort: patients must have progressed while on treatment with an EGFR TKI (T790M directed EGFR TKIs are permitted). Other prior lines of therapy may have been given.

Part D cMET-ve patients:

No prior treatment with a 3rd generation TKI, T790M negative:

Patients must have received at least one prior line of therapy with 1st or 2nd generation EGFR TKI, but not a 3rd generation (T790M directed) EGFR TKI.

cMET status: Prior to study entry, local confirmation of tumour cMET status is acceptable, a central result will be confirmed retrospectively. If a local test is not available, central confirmation of tumour cMET status must be obtained prior to study entry.

T790M status: Local confirmation of tumour T790M status is acceptable, a central result will be confirmed retrospectively. If local testing is performed with the Cobas® EGFR Mutation Test, the central confirmation is not required.

At least one lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI which is suitable for accurate repeated measurements

WHO performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks

Females should be using adequate contraceptive measures, must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential.

Exclusion Criteria (summary):

Treatment with an EGFR TKI within approximately 5x half-life of the first dose of study treatment. Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment. Patients currently receiving (or unable to stop use) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior). For AZD6094 patients currently receiving (or unable to stop use at least 2 weeks) prior to receiving the first dose, medications known to be strong inhibitors of CYP1A2. Prior AZD9291 dosing in the present study. Prior or current treatment with AZD6094 or another cMET inhibitor (if allocated to AZD9291 + AZD6094). Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation which must be completed within ≥4 weeks of the first dose of study treatment. Major (or anticipated major) surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study treatment. Currently receiving treatment with warfarin sodium.

With the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy, any unresolved toxicities from prior therapy and/or pre-study biopsies greater than CTCAE Grade 1 at the time of starting study treatment.